PROJECT SUMMARY COVID-19 is a devastating disease caused by the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV2) that has resulted in 100,442 deaths in the U.S. (May 28th, 2020). Smell loss is a major symptom for COVID-19 (1-4). In a recent publication we identified TRPM5-expressing cells (microvillous cells (MVCs) and olfactory sensory neurons (OSNs)) as viral-responding cells in the olfactory epithelium (OE)(5). MVCs are part of a family of TRPM5-expressing cells found in the airways and the intestine that respond to virus, bacteria and irritants with a type 2 immune response through IL-25 and release of acetylcholine (6, 7). In preliminary studies we find that intranasal herpes simplex virus type 1 (HSV-1) infection in mice elicits a dramatic shift in TRPM5 expression from MVCs to the basal epithelium consistent with activation of stem cells (SCs) for immune defense, as proposed for chronic inflammation of the OE (8-10) expression However, inflammation It is unclear whether this increased and altered location of TRPM5 is an aberrant response, contributing to persistent inflammation. influenza infection increases TRPM5 expressing cells in the lung, leading to damaging persistent (11) Here . . we hypothesize that SARS-CoV-2 infection of OE upregulates TRPM5 expression, leading to proinflammatory cytokine release, decrease in OSN numbers and activity, persistent inflammation yet ineffective viral clearance leading to worse COVID-19; whereas addition of TRPM5 blockers will attenuate cytokine release and viral loads. We epithelial flufenamic will test this hypothesis with studies of changes in inflammation and olfactory function in human olfactory cell cultures infected with by inhibition of TRPM5 using the FDA approved drug acid in two specific aims: SARS-CoV2 Aim 1. Determine if activation of the TRPM5 transduction cascade in MVCs mediates the inflammatory response to SARS-CoV-2 viral infection leading to loss of olfactory function. Aim 2. Determine if TRPM5 expression in the OE promotes SARS-CoV-2 neurotropism, facilitating nervous system disease.